Ultrafiltration (UF) and diafiltration (DF) are pressure-driven membrane separation processes which are used to separate (by a sieving mechanism) macromolecules such as proteins from solutions containing solvents and low MW solutes. Ultrafiltration and diafiltration processes are similar and identical membranes are used for both. In UF, no additional solvent (water) is added to the solution which is being filtered while filtration is in progress; in DF additional solvent is added during filtration. If a solution contains macromolecules of sufficiently great size differences, then (UF) or (DF) can also be used to fractionate these macromolecules.
The filtration regime which comprises UF or DF lies on the spectrum of pressure driven membrane separation processes between hyperfiltration (HF), also known as reverse osmosis, on its fine-pored side and microfiltration (MF) on its coarse-pored side. The UF regime covers the pore diameter range between 0.001 and 0.02 .mu.m (10-200 .ANG.). Ultrafiltration is also described in terms of the molecular weigh cutoff (MWCO) capabilities of its membranes. It consists of membranes with MWCO between about 500 and several million.
Asymmetric, integrally-skinned UF membranes are prepared by a generalized process know as phase inversion in which a multicomponent polymer solution (sol) consisting (usually) of three components: polymer, solvent, and poreformer (nonsolvent, swelling agent, or weak solvent) is induced to separate into two interdispersed liquid phases prior to coagulation into a solid membrane gel. To effect the separation into two interdispersed liquid phases, polymer miscibility in the solvent vehicle is lowered by one of these techniques:
1.) Solvent evaporation (Dry Process); PA1 2.) Exchange of solvent for nonsolvent (Wet Process); and PA1 3.) Lowering solution temperature (thermal process). PA1 (1) the composition of the initial solution, PA1 (2) the composition of the setting bath, and PA1 (3) the rate at which the casting resin is mixed, PA1 (4) the casting solution temperature, or the spinning temperature, in response to said measurement.
Two general structural varieties of asymmetric, integrally-skinned, phase inversion UF membranes are known in the art. Representative of the first is U.S. Pat. No. 3,615,024, which is the original and still most commonly encountered variety of ultrafiltration membrane, consisting essentially of a bilayer having a thin skin exhibiting what has been termed slit-like fissures or cracks, and a thick substructure containing a high concentration of finger-like intrusions or macrovoids. The macrovoids often extend from one surface to the other although they are sometimes buried more deeply within the matrix. Ideally, an integral skin covers the macrovoids but, in practice, some of the skin above the macrovoids is cracked, thereby breaking the integrity of the skin and enabling the passage of large particles. These membranes are supplied wetted with a pore supporting fluid since they cannot tolerate full dryness without severe loss of filtration performance. Bacteriostats, which must be washed out of the membrane before usage, are often present in membranes that are supplied wet. Some manufacturers indicate in their catalogs that a membrane is being supplied "dry", however these membranes may contain humectants such as glycerol as a pore supporting fluid. As with bacteriostats, humectants must be removed from the membrane by soaking, flushing or by some other method that never permits the membrane to become fully dried.
Representative of the second general type of ultrafiltration membrane is that obtained in accordance with U.S. Pat. Nos. 4,954,381 and 4,451,424), which purportedly produce integrally-skinned UF membranes with macrovoid-free matrices by increasing the viscosity of the casting solution through the addition of water soluble viscosity enhancing polymeric additives such as polyvinylpyrrolidone (PVP) or polyethyleneglycol (PEG). These membranes exhibit a skin with a pore size distribution which is too broad to be integrity-tested because of the leaching out of the polymeric additives during precipitation and washing steps, as well as during their use in the UF process. These membranes can be supplied "dry" (ie. no free liquid present), but contain high concentrations of residual PVP or PEG. Humectants such as glycerol, PVP, PEG and/or water and other wetting fluids may act as plasticizers to diminish friability. These materials may also act as pore supporting fluids which if removed lead to cracks and other defects in the membrane skin.
Additionally, the pore size increases with the molecular weight (MW) of the extractable additive, which is in turn related to the breadth of the pore size distribution of these membranes.
Although widely used, ultrafiltration membranes are recognized to suffer from some serious drawbacks. For example, nearly all ultrafiltration/diafiltration membranes contain a humectant such as glycerol or must be maintained in a wetted state at all times, including during shipping, because the filtration properties of the membrane are unstable owing to the presence of defects. Once the humectant or other supporting liquid is removed and the membrane is dried and rewetted, the performance is altered and the membrane skin becomes cracked and the membrane useless. This means that as a practical issue, all ultrafiltration/diafiltration membranes must be shipped along with a large amount of wetting liquid, usually water, increasing shipping costs. Further, the requirement that the membrane be maintained in a wetted state also is a substantial burden on the users who must assure that the membrane is never allowed to dry. The fact that the membranes are constantly maintained in a wetted state also means that the risk of bacterial growth is present, requiring then that a bacteriostat, or the like, be present in the wetted membrane. Unfortunately, the presence of a bacteriostat also introduces the problem of contamination of the product stream by the membrane, for once such an agent is present, it is difficult, if not impossible to remove.
In the case of membranes containing a humectant such as glycerol, the membrane must be soaked in several changes of water or other solvent in order to remove as much of the foreign material as possible. Then once the pore structure is supported with the solvent the sample must never be permitted to dry out.
Another significant problem with all currently available ultrafiltration/diafiltration membranes is the presence of significant defects in the membrane. Such defects include macrovoids, cracks, pinholes, and other defects and imperfections that either breach the skin layer or lead to failure of the membrane. The presence of such defects means, however, that although a given membrane may be rated with a removal rating that would indicate, for example, that the membrane is capable of removing materials of moderate molecular weight (between 1,000 to 500,000) from a liquid, the presence of the defects allows a given portion of the substances to pass through the membrane, which, of course, is very undesirable. Even relatively large particles such as latex spheres are known to pass through UF membrane defects.
Molecular weight cutoff is an expression of the retention characteristics of a membrane in terms of molecules of known sizes. Retention is commonly rated as that molecular weight cutoff at which at least 90 percent of spherical uncharged molecules of that same molecular weight will be retained by the porous membrane, whereas less than about 50 percent of such molecules of significantly lower molecular weight will be retained. However, linear molecules with molecular weights greater than the molecular weight cutoff may pass through the membrane because the effective diameter of a linear molecule is smaller than that of a spherical molecule. Linear molecules may approach a membrane pore "end on" and thread themselves through the pore. This can occur if a long chain linear molecule is aligned with the laminar flow lines of the fluid passing through the membrane. On the other hand, charged molecules less than the molecular weight cutoff may not pass through the membrane due to electrostatic interactions with the membrane. In ultrafiltration membranes, the molecular weight cutoff ranges from about 500 or 1000 up to about several million corresponding to pore sizes of 10 to 200 .ANG..
Although a limited number of ultrafiltration membranes have been recently introduced in the form of hollow fibers, with indicated nominal molecular weight cutoff ratings in the 1,000 to several million range, which membranes are capable of being shipped in the dry state, such membranes still suffer from the very significant problem of having defects in their structure, rendering them of only limited value.
Because of the wide and large number of applications for ultrafiltration membranes, considerable effort has been spent to improve the effectiveness of such membranes, but to date, with limited success. Many patents and articles have been published regarding the manufacture of ultrafiltration membranes, some claiming them to be "defect-free", and some claiming them to be dryable, but the fact remains that no ultrafiltration membrane has heretofore been produced that is both dryable and which is free of defects.
Present-day ultrafiltration membranes work on a statistical basis, ie. as only a small portion of liquid being filtered passes through defects in the membrane, and as only a portion of all liquid being filtered contains the material to be removed, the probability is that only a small amount of the material to be removed will pass through the membrane. If, however, the material being filtered is, for example, a pharmaceutical composition and the material to be removed is a bacterium, and bacteria does pass through the membrane, the patient who becomes ill by using the contaminated product will not care very much about probabilities.
Again, the problem with ultrafiltration membranes made in accordance with any of the prior art processes is that they are not capable of being dried without a humectant supporting the pore structure and/or they are not free of the various defects described earlier, rendering them of only limited value.
Further, as with many processes for manufacturing membranes, absolute predictability of the performance and the quality of the finished product is not possible, hence a method of testing the integrity of the finished membrane product is needed. Unfortunately, there presently is no useful way to test the integrity of an ultrafiltration membrane, and certainly no rapid way to do so. With respect to microfiltration membranes and other types of porous filter media, the tests known as the "bubble point" (ASTM F316-86) and the K.sub.L (U.S. Pat. No. 4,340,479) methods have been employed for many years to characterize the porosity of such structures. However, due to the extremely small pore sizes encountered in ultrafiltration membranes neither the K.sub.L nor the "bubble point" test can be applied successfully. As the pore size of a membrane decreases, the pressure required to carry out a "bubble point" or K.sub.L test increases. On an ultrafiltration membrane such test pressures would crush or otherwise damage the membrane.
In the case of ultrafiltration membranes generally, there is considerable difficulty in directly observing and measuring pores and pore sizes, as by scanning electron microscopy, for example. It has become common in the art to employ molecular weight cutoff values as discussed above, as an inferential and indirect technique for the determination of pore sizes. As a general proposition, the functional diameter of pores is approximately equal to the cube root of the molecular weight of the largest generally spherical, globular molecule, free of electric charge, which can pass through the membrane, while by convention the size of the smallest such molecule which is retained to the required extent of 90 percent represents the molecular weight cutoff. These determinations are well known to those of ordinary skill in the art. Clearly, however, such a test provides only approximations of the true porosity of any given ultrafiltration structure and, further, is not a test that may be rapidly employed. The measurement of molecular weight cutoffs is also fraught with complications such as the adsorption of the test substance on the membrane surfaces accompanied by the plugging of the sample during the test. A typical molecular weight cutoff test could require hours or even days to complete. Instead of characterizing membranes in terms of some standard test parameter such as K.sub.L or pore size, broad ranges of molecular weight cutoff are generally cited in product catalogs and in the technical literature.
Because a reliable, rapid test for evaluating the integrity, molecular weight cutoff and pore size rating of ultrafiltration membranes is an absolute necessity for the reliable, consistent production of UF/DF membranes, a great need exists for such a test.